HBV chronically infects 400 million people worldwide and leads to a high incidence of severe liver complications, including cirrhosis and hepatocellular carcinoma (HCC), in these patients. HCC is a leading cause of death worldwide and is one of the most difficult cancers to treat, only a small number of patients qualifying for curative therapies.
It is believed that HBV itself is not highly cytopathic and that the chronic liver injury and HCC development are secondary to an antiviral cellular immune response. However, progress in understanding the immunopathogenic mechanisms of HBV-associated liver diseases has been hampered by the lack of a convenient small animal model. Chimpanzees are susceptible to HBV infection, but only develop a mild liver inflammatory reaction, and their use in laboratory research is further limited because of ethical and financial considerations. Studies of HBV-related viruses in woodchucks, ground squirrels, and ducks have improved our knowledge of HBV virology and the development of antiviral agents, but have not led to a better understanding of HBV immunopathology. Similarly, HBV transgenic mice produce infectious HBV from the chromosome-integrated viral genome, but are centrally tolerant to viral antigens and do not develop liver diseases. A refinement of this latter system, involving the injection of immunocompetent mice with a plasmid containing a full-length HBV genome, resulted in transient or long-term HBV replication in the liver, but caused only limited hepatitis. Adoptive transfer of unprimed splenocytes into HBV transgenic mice on a severe combined immunodeficiency background generated chronic hepatitis with fluctuations in alanine aminotransferase (ALT) levels but the liver disease was mild and did not progress to HCC, possibly due to the lack of regeneration of HBV-specific T cells in the host.
Therefore, there is an urgent need to produce a chronic HBV disease model in an immune competent animal to facilitate elucidating the cause-and-effect relationships of chronic HBV diseases.